tbuckley/cabot-search huggingface dataset:
Abstract 311: Development of cludin-3 specific human monoclonal antibody(ABN501) as therapeutic anti-tumor agents
Authors: Hong-Seok Choi, Euni Sim, Na Young Kim, Yong Jin Lee, Sae Hyung Lee, Hayeon Park, Hobin Yang, Jiwon Jo, Myeung-Ryun Seo, Heegeon Park, Ji-Hye Lee, Sungyoul Hong, Young Kee Shin, Jun-Young Choi
Journal: Cancer Research (2022)

Abstract The tight junctions of epithelial tissues, that most malignant tumors are derived from, are associated in cell-cell interactions. Among the tight junction proteins, claudin-3 (CLDN3) is overexpressed in many types of solid cancers, such as breast, ovarian, colorectal, and gastric cancers. Although CLDN3 can be potential therapeutic target due to the overexpression in various types of cancers, high homology with other CLDN family members is a hurdle to develop antibodies specifically targeting CLDN3. In this study, human IgG1 monoclonal antibody (ABN501) against CLDN3 was developed by scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. It was confirmed that ABN501 specifically bound to human and mouse CLDN3 without cross-reactivity to other CLDN family members. Sub-nanomolar affinity in binding kinetics of ABN501 was measured in CLDN3 expressing cell lines. We observed the antibody-dependent cytotoxicity (ADCC) activity of ABN501 with human NK cells expressing CD16a (NK-92MI-CD16a), in various cancer cell lines according to CLDN3 expression levels. We also confirmed that ABN501 specifically targeted CLDN3-expressing tumors in biodistribution assay using fluorescence-conjugated ABN501. In addition, ABN501 showed anti-tumor effects when treated with NK-92MI-CD16a in xenograft mice bearing CLDN3 expressing tumors. Taken these results together, we suggest that ABN501, specifically recognizing to CLDN3, can be used as therapeutic agents for CLDN3 positive cancer, and developed in many different forms to treat cancers with its specificity for cancer diagnosis, antibody-drug conjugates, and chimeric antigen receptor (CAR) immunotherapy. Citation Format: Hong-Seok Choi, Euni Sim, Na Young Kim, Yong Jin Lee, Sae Hyung Lee, Hayeon Park, Hobin Yang, Jiwon Jo, Myeung-Ryun Seo, Heegeon Park, Ji-Hye Lee, Sungyoul Hong, Young Kee Shin, Jun-Young Choi. Development of cludin-3 specific human monoclonal antibody(ABN501) as therapeutic anti-tumor agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 311.
Abstract 2880: CD133-targeting silicate prodrug nanoparticles for effective cancer stem cell targeting
Authors: Shubhmita Bhatnagar, Mengyuan Jin, Thomas Hoye, Jayanth Panyam
Journal: Cancer Research (2022)

Abstract Cancer stem cells (CSCs) are considered to be key contributors to drug resistance and tumor recurrence in many solid tumors. Therapeutic approaches that specifically target these cells are needed to improve treatment outcomes in these tumor types. We are investigating CD133, a widely used surface marker to identify CSCs in colon, brain, and breast tumors. Here, we report the use of polymeric nanoparticles targeting CD133 by conjugating an anti-CD133 scFv-Fc to poly(L-lactide)-PEG-maleimide nanoparticles (anti-CD133 NPs) for effective CSC targeting. The Fc tagged anti-CD133 scFv was prepared and purified using an Expi293 expression system. Nanoparticles were prepared using flash nanoprecipitation and loaded with a hydrophobic, hydrolytically labile, silicate prodrug of paclitaxel. Flash nanoprecipitation allowed for generation of particles with a size of 232 ± 17 nm (increased to 289 ± 23 nm upon scFv conjugation), a zeta potential of -11.5 mV and a drug loading of 57 ± 8 wt% measured by HPLC. The anti-CD133 scFv-Fc was thiolated using 2-iminothiolane (2-IT) and conjugated to nanoparticles using thiol-maleimide chemistry. Thiolation of the antibody was optimized using different molar excesses of 2-IT. A binding assay using Caco-2 cells (which overexpress CD133) confirmed that thiolation of the antibody did not affect its binding, even at the highest molar excess of 2-IT used. With 200x molar excess of 2-IT, 2.9 thiols per antibody were added. Antibody conjugation was confirmed using gel electrophoresis; bands corresponding to the heavy and light chains of antibody were observed for anti-CD133 NPs after reduction but were not seen for non-reduced anti-CD133 NPs or for unconjugated particles. Cytotoxicity studies in MDA-MB-231-LM2 cells revealed maximum kill in drug loaded anti-CD133 NPs, which was significantly higher than for either non-targeted, drug-loaded nanoparticles or blank nanoparticles (p&amp;lt;0.05). Overall, these studies indicate the potential for using anti-CD133 scFv-Fc in conjunction with FNP-produced silicate prodrug nanoparticles of paclitaxel for efficient targeting of CSCs. Citation Format: Shubhmita Bhatnagar, Mengyuan Jin, Thomas Hoye, Jayanth Panyam. CD133-targeting silicate prodrug nanoparticles for effective cancer stem cell targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2880.
Satellite repeat RNA expression in epithelial ovarian cancer associates with a tumor-immunosuppressive phenotype
Authors: Rebecca L. Porter, Siyu Sun, Micayla N. Flores, Emily Berzolla, Eunae You, Ildiko E. Phillips, Neelima KC, Niyati Desai, Eric C. Tai, Annamaria Szabolcs, Evan R. Lang, Amaya Pankaj, Michael J. Raabe, Vishal Thapar, Katherine H. Xu, Linda T. Nieman, Daniel C. Rabe, David L. Kolin, Elizabeth H. Stover, David Pepin, Shannon L. Stott, Vikram Deshpande, Joyce F. Liu, Alexander Solovyov, Ursula A. Matulonis, Benjamin D. Greenbaum, David T. Ting
Journal: Journal of Clinical Investigation (2022)

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression — and its correlation with EMT and anticorrelation with IFN-response genes — was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance.
Abstract 3398: Exploring the biology of ctDNA release in colon cancer
Authors: Judit Kisistok, Tenna Vesterman Henriksen, Jesper Bertram Bramsen, Thomas Reinert, Trine Block Mattesen, Nicolai Juul Birkbak, Claus Lindbjerg Andersen
Journal: Cancer Research (2022)

Abstract Background: Colorectal cancer is responsible for 9.4% of cancer-related deaths worldwide. Early detection of the disease has the potential to improve patient outcomes, therefore, developing an efficient and minimally invasive method for carrying out surveillance has been a clinically relevant effort in recent years. Circulating tumour DNA has garnered interest as a marker for early cancer detection, however, deeper understanding of the underlying biology of ctDNA release is needed in order to maximize its utility in clinical practice. In this project, we aimed to investigate whether a phenotype conductive to ctDNA shedding can be defined in a colorectal cancer cohort, including transcriptomic, genomic and clinical data collected from stage I to stage IV colon cancer patients at Aarhus University Hospital. Methods: Transcriptomic data from 102 patients and whole exome sequencing data from 60 patients were analyzed. Differential gene expression and differential pathway enrichment analyses between ctDNA positive and ctDNA negative patients were conducted by performing Student’s t-test. The resulting p-values were adjusted according to the Benjamini-Hochberg method. The genes in the transcriptomic analyses were assigned to pathways with regard to the MSigDB Hallmark gene sets and pathway enrichment was assessed using Gene Set Variation Analysis (GSVA). Using an extended cohort of 537 patients, we performed Wilcoxon’s signed rank test to investigate the association between tumour size, histological subtypes and ctDNA shedding behavior. Additionally, we modelled the expected ctDNA fraction as a function of birth rate, death rate and tumour mass. Results: In colon cancer, ctDNA release is primarily associated with tumour size, molecular subtypes and proliferative transcriptomic signatures. A moderate but significant correlation was observed between the tumour’s largest diameter and the detected ctDNA fraction. Furthermore, molecular subtypes associated with less aggressive disease tended to shed lower amounts of ctDNA. Notably, we have found that pathways associated with proliferation are enriched in the ctDNA positive subgroup. Conclusions: Our results demonstrate that enhanced proliferative capacity in connection with tumour size and molecular subtypes may contribute to a higher ctDNA release rate. We anticipate our study to be a starting point for further investigation of ctDNA shedding dynamics in colorectal cancer. Citation Format: Judit Kisistok, Tenna Vesterman Henriksen, Jesper Bertram Bramsen, Thomas Reinert, Trine Block Mattesen, Nicolai Juul Birkbak, Claus Lindbjerg Andersen. Exploring the biology of ctDNA release in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3398.
Abstract ND14: Pharmacological profile and anti-tumor properties of FHD-286: A novel BAF inhibitor for the treatment of transcription factor-driven cancers
Authors: Murphy Hentemann
Journal: Cancer Research (2022)

Abstract Pharmacological profile and anti-tumor properties of FHD-286, a novel BAF inhibitor for the treatment of transcription factor-driven cancersMartin Hentemann, Rishi G. Vaswani, Lan Xu, Richard C. Centore, Luis M. M. Soares, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy Setser, David L. Lahr, Laura Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Sarah Reilly, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, Ammar Adam, David Huang, Shawn Schiller, Kevin Wilson, Liyue Huang, Jessica Piel, Johannes Voigt, David S. Millan, Ho Man Chan, Ryan G. Kruger, Carl P. Decicco, Samuel Agresta, Steven F. BellonFoghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, MA 02139The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its ATP-dependent chromatin remodeling activity, BAF regulates the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. We have discovered and developed a compound that potently and selectively inhibits the ATPase components of the BAF complex, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). Mutational, structural, and biochemical studies demonstrated that this SMARCA4/SMARCA2 inhibitor acts through a unique allosteric mechanism. Pharmacologic inhibition of the BAF complex resulted in lineage-specific changes in chromatin accessibility in cancer cell lines from diverse origins. Phenotypic screening of cancer cell lines showed that uveal melanoma and hematological cancer cell lines were exquisitely sensitive to BAF inhibition. FHD-286 is orally bioavailable and demonstrates robust efficacy in multiple cell line and primary human tumor derived xenograft models at well-tolerated doses. In preclinical efficacy and toxicology studies, this first in class molecule demonstrates an acceptable therapeutic index which should allow for flexibility in clinical designs. FHD-286 is currently in two Phase I trials for both relapsed refractory AML and MDS, and metastatic uveal melanoma. Citation Format: Murphy Hentemann. Pharmacological profile and anti-tumor properties of FHD-286: A novel BAF inhibitor for the treatment of transcription factor-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND14.
Abstract 938: Characterization of a murine pancreatic ductal adenocarcinoma (PDAC) model with tamoxifen inducible pancreas-specific blockade of transforming growth factor-β (TGF-β) signaling with KrasG12D expression
Authors: Sanjay Pandey, Brett Bell, Claudia G. Chavez, Wade Koba, Talicia Savage, Patrik Asp, Indranil Basu, Chandan Guha
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a five-year overall survival of less than 10%. The lack of effective therapeutic strategies for PDAC necessitates the development of models to better understand the disease. Transforming growth factor-β (TGFβ)-SMAD4 signaling plays a critical role in PDAC development with more than half of all patients either have mutated SMAD4 (loss of function) or altered type II TGF TGFβ -receptor (Tgfbr2) gene. Here we present a murine model of PDAC with Tamoxifen induced conditional deletion of the TGFβ-receptor 2 (Tgfbr2) gene and expression of an activating KrasG12D mutation in pancreatic acinar cells. LSL-KrasG12D/+; Tgfbriifl/fl; Ptf1a-CreER mice were generated by crossing Ptf1aCre-ERTM mice with LSL-KrasG12D mice in which expression of KrasG12D is restrained by a lox-stop-lox cassette until Cre activation by tamoxifen injection. These mice were then bred with Tgfbr2fl/fl mice with loxP sites flanking exon 4 of the Tgfbr2 allele to block TGFβ-SMAD4 signaling. 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography was performed to detect tumors and measure their metabolic volumes and standard uptake values over time. This model showed a latency of approximately 16-20 weeks following 5 i.p. injections of tamoxifen (~75 mg/kg in corn oil). Follow-up on the survival of the mice post tamoxifen injections showed the median survival of 252 days in male and 234 days in female mice. Histological evaluation showed multifocal nodules of neoplasia composed of tubules and acini with cuboidal to polygonal cells. Carcinoma cells were positive for cytokeratin 19 and for mucins identified by Alcian blue staining, both confirming the ductal phenotype of these tumors. Picrosirius red staining demonstrated dense stromal desmoplasia which recapitulates human disease. Flow cytometric evolution of the immune microenvironment was also done to evaluate the infiltration of immune cells. Additional characterization of our novel mouse model of pancreatic cancer is underway to understand PDAC progression and develop effective therapeutic approaches. Citation Format: Sanjay Pandey, Brett Bell, Claudia G. Chavez, Wade Koba, Talicia Savage, Patrik Asp, Indranil Basu, Chandan Guha. Characterization of a murine pancreatic ductal adenocarcinoma (PDAC) model with tamoxifen inducible pancreas-specific blockade of transforming growth factor-β (TGF-β) signaling with KrasG12D expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 938.
Abstract 2669: ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models
Authors: Leenus Martin, Erin D. Lew, Roopal Patel, Joanne Oh, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Wei Lin, Les Brail, Robert Shoemaker
Journal: Cancer Research (2022)

Abstract KRAS mutations occur in about 25% of all cancers and promote oncogenesis via constitutive activation of the RAS/MAPK pathway. Targeting KRAS mutant tumors by inhibiting individual nodes in the RAS/MAPK pathway, including SHP2, SOS1, KRAS, RAF, MEK, and ERK, has shown early clinical activity, but the rapid emergence of resistance limits the benefit of monotherapy. Resistance is often mediated by reactivation of RAS/MAPK pathway signaling, which can occur by increased activation of upstream of the RAS/MAPK pathway (e.g., EGFR activation) and/or activation of RAS/MAPK pathway nodes (e.g., oncogenic BRAF and MEK mutations). Inhibiting both upstream and downstream RAS/MAPK pathway nodes has the potential to more robustly prevent reactivation relative to inhibition of a single node alone. We are currently exploring the combination of an inhibitor of an upstream node, SHP2, with ERAS-601 and the terminal downstream node, ERK1/2, with ERAS-007 (our first “MAPKlamp”) in nonclinical models. We evaluated this MAPKlamp in NSCLC, CRC, and pancreatic tumor models that harbored KRAS mutations in vitro and in vivo. In 14-day clonogenic assays in KRAS mutant NSCLC, CRC, and PDAC cell lines, this MAPKlamp inhibited colony growth more potently than ERAS-601 or ERAS-007 alone. In KRAS mutant CDX and PDX models, this MAPKlamp’s in vitro activity was observed in vivo where it achieved superior tumor growth inhibition and tumor regression relative to ERAS-601 and ERAS-007 monotherapy. This MAPKlamp showed in vitro and in vivo combination activity in KRAS mutant tumors, and these results support its clinical evaluation in RAS/MAPK pathway-driven tumors. Citation Format: Leenus Martin, Erin D. Lew, Roopal Patel, Joanne Oh, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Wei Lin, Les Brail, Robert Shoemaker. ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2669.
Abstract 2287: Dissecting the heterogeneity of central nervous system hemangioblastomas by single-cell and single-nuclei RNA sequencing
Authors: Eumorphia Konstantakou, Elizabeth Perez, Alex Barbera, Nicholas Haradhvala, Marcello Stanzione, Fred Barker, Brian Nahed, Anat Stemmer-Rachamimov, Nick Dyson, Gad Getz, Mario Suva, Othon Iliopoulos
Journal: Cancer Research (2022)

Abstract Hemangioblastomas (HBs) are highly vascular tumors of the Central Nervous System that are commonly associated with the familial von Hippel-Lindau (VHL) disease and contribute significantly to the morbidity and mortality of VHL patients. They are characterized by high heterogeneity but the cell origin of HB tumors is still unclear, and the genomic landscape and signaling pathways underlying the tumor formation are unknown. We performed single-cell and single-nuclei RNA sequencing of cerebellar and spinal HBs surgically removed from VHL patients, in order to identify the lineage of the tumor cells and to profile the tumor microenvironment (TME). The percentage of VHL-/- tumor cells ranges from 8-80% of the cell population; the TME is reactive, contributing to a high percentage of the total tumor volume and playing a critical role in HB development. Single-cell and single-nuclei HB analysis provided significant insights into the cell of origin as well as the oncogenic pathways that drive the growth of HB. Whole exome sequencing (WES) in a cohort of HB patients revealed that biallelic VHL inactivation is necessary for the tumor formation of VHL disease-related HBs. Citation Format: Eumorphia Konstantakou, Elizabeth Perez, Alex Barbera, Nicholas Haradhvala, Marcello Stanzione, Fred Barker, Brian Nahed, Anat Stemmer-Rachamimov, Nick Dyson, Gad Getz, Mario Suva, Othon Iliopoulos. Dissecting the heterogeneity of central nervous system hemangioblastomas by single-cell and single-nuclei RNA sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2287.
Abstract 2174: Sirpiglenastat (DRP-104), a novel broad acting glutamine antagonist, has therapeutic potential in targeting KEAP1-mutant lung cancer
Authors: Sarah LeBoeuf, Ray Pillai, Shih Ming Huang, Triantafyllia Karakousi, Warren Wu, Volkan Sayin, Robert Wild, Thales Papagiannakopoulos
Journal: Cancer Research (2022)

Abstract Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge for clinical oncology. Approximately 20% of KRASmutant LUAD tumors carry loss-of-function mutations in KEAP1, a negative regulator of NRF2, which is the master transcriptional regulator of the endogenous antioxidant response. Emerging clinical studies demonstrate that KEAP1-mutant tumors are refractory to standard-of-care chemotherapy, immunotherapy, radiation and more recently KRASG12C inhibitors. Using a genetically engineered mouse model of KRAS-driven LUAD we demonstrated that loss of Keap1 hyper-activates Nrf2 and accelerates KRAS-driven LUAD. We observe that the ability of KEAP1 mutant tumors to divert their metabolism towards antioxidant production comes with a cost, generating multiple metabolic vulnerabilities, including a dependency on glutamine metabolism that can be therapeutically exploited through the pharmacological inhibition of glutaminase and other glutamine metabolizing enzymes. Using sirpiglenastat (DRP-104), a novel broad acting glutamine antagonist which inhibits all glutamine-consuming reactions, we demonstrate robust anti-tumor efficacy in multiple mouse and human pre-clinical KEAP1-mutant NSCLC models. Furthermore, we have characterized the metabolic mechanisms underlying DRP-104 sensitivity. Our studies demonstrate that DRP-104 has a distinct and broader mechanism of action compared to glutaminase selective inhibition, suggesting broader inhibition of glutamine metabolism may be a more effective therapeutic approach against KEAP1-mutant tumors. We have recently demonstrated that KEAP1-mutant tumors evade anti-tumor immune responses and do not respond to immune checkpoint blockade, which is also supported by clinical observations. We are currently assessing whether DRP-104 is able to promote anti-tumor immune responses as a single agent or in combination with immune checkpoint blockade in KEAP1-mutant tumors. Our studies will provide a rationale for sub-stratification of KEAP1-mutant patients with hyperactivation of the NRF2 pathway, which is a genetic subset of NSCLC with great clinical need, as treatment candidates for sirpiglenastat. A first-in-human clinical trial of sirpiglenastat (DRP-104) is currently ongoing and will further explore this hypothesis in a LUAD cohort (NCT04471415). Citation Format: Sarah LeBoeuf, Ray Pillai, Shih Ming Huang, Triantafyllia Karakousi, Warren Wu, Volkan Sayin, Robert Wild, Thales Papagiannakopoulos. Sirpiglenastat (DRP-104), a novel broad acting glutamine antagonist, has therapeutic potential in targeting KEAP1-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2174.